The Indiana University interactive research program project (IU-IRPG) is one of eight proposed IRPGs whose long-term goal is the elucidation of heritable phenotypes and underlying genetic mechanisms that contribute to alcoholism (alcohol dependence) susceptibility and severity. To this end, the relationships among established and potentially alcoholism-relevant phenotypic traits and their association and linkage to candidate genes and quantitative trait loci (QTLs) will be studied in a cohort of densely affected and control families from ethnically diverse populations. In the proposed studies, the heritability of quantitative measures of central nervous system (CNS) disinhibition will be determined and correlated with clinical diagnoses of predisposing and/or comorbid Axis I and II psychiatric disorders. Intermediate phenotypes considered to be fundamental elements of alcohol dependence will be assessed using quantitative scales, their heritability determined, and their relationship to severity of alcoholism analyzed. The genes that underlie these phenotypes will be sought through a genome wide survey and candidate gene association studies. The IU-IRPG proposes to ascertain a fair share of the genetically informative population necessary for these goals and to assess them for novel phenotypes of neural disinhibition. In addition, we will use the BrAC clamping procedure to define novel phenotypes of the acute response to alcohol and the alcohol elimination rate. We will estimate the heritability of these phenotypes and of the quantitative clinical phenotypes relating to quantity-frequency of drinking, tolerance, loss of control, craving for alcohol, and physical withdrawal. Finally we will contribute half the genotyping and genetic analyses required to test our hypotheses, and will provide data management services for portions of the IRPG database.